Differential Activation of Human and Mouse Toll-Like Receptor 4 by the Adjuvant Candidate LpxL1 of<i>Neisseria meningitidis</i>

Steeghs, Liana; Keestra, A. Marijke; Mourik, Andries van; Uronen-Hansson, Heli; Ley, Peter van der; Callard, Robin E.; Klein, Nigel; Putten, Jos P. M. van

doi:10.1128/iai.00005-08

Cited by 72 publications

(54 citation statements)

References 39 publications

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“…We have described previously that the pentaacylated LPS from an lpxL1 Ϫ mutant of N. meningitidis, lacking the secondary C12:0 acyl chain at the 2Ј-position of lipid A, has reduced endotoxicity but similar adjuvant activity in mice as compared with wild-type meningococcal LPS (14,39). However, the lpxL1 Ϫ LPS was more strongly reduced in its ability to activate human as compared with murine TLR4, as measured by the expression of the NF-B transcription factor and various MyD88-dependent cytokines (40). For PagL-deacylated meningococcal LPS, adjuvant activity has also been demonstrated in mice, but it should be noted that in this animal species there is very little difference in endotoxic activity compared with wild-type hexaacylated LPS (41).…”

Section: Discussionmentioning

confidence: 92%

Lipopolysaccharide Engineering in Neisseria meningitidis

Pupo

Hamstra

Meiring

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 92%

Lipopolysaccharide Engineering in Neisseria meningitidis

Pupo

Hamstra

Meiring

et al. 2014

Journal of Biological Chemistry

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“…The extracellular domains of mouse and human TLR4 show only 62% sequence similarity, while the hypervariable ligand binding regions have only 48% sequence similarity (9,47). Moreover, species differences for MD-2, the coreceptor for TLR4, also affect the ligand recognition (48,49) and the structural basis for these species differences has been resolved (50), which highlights the differences in PAMP recognition between mouse TLR4 and human TLR4 (51)(52)(53)(54). Added to this are the TLR4 cellular expression patterns and tissue distributions.…”

Section: Discussionmentioning

confidence: 98%

Human Coagulation Factor X-Adenovirus Type 5 Complexes Poorly Stimulate an Innate Immune Response in Human Mononuclear Phagocytes

Eichholz

Mennechet

Kremer

2015

J Virol

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One of the first lines of host defense against many viruses in vertebrates is the innate immune system, which detects pathogenassociated molecular patterns (PAMPs) using pathogen recognition receptors (PRR). The dynamic interactions between pathogens and hosts create, in some cases, species-specific relationships. Recently, it was shown that murine factor X (mFX)-armored human adenovirus (HAd) stimulated a mFX-Toll-like receptor 4 (TLR4)-associated response in mouse macrophages in vitro and in vivo. Given the importance of studies using animals to better understand host-pathogen interactions, we asked if human FX (hFX)-armored HAd type 5 (HAd5) was capable of activating innate immune sensors in primary human mononuclear phagocytes. To this end, we assayed human mononuclear phagocytes for their ability to be stimulated by hFX-armored HAd5 via a TLR/NF-B pathway, in particular, a TLR4 pathway. In our hands, we found no significant interaction, activation, or maturation of human mononuclear phagocytes caused by the presence of hFX-armored HAd5. IMPORTANCEAnimals, and mice in particular, are often used as informative and powerful surrogates for how pathogens interact with natural host systems. When possible, extended and targeted studies in the natural host can then be performed. Our data will help us understand the differences in preclinical testing in mice and clinical use in humans in order to improve treatment for HAd diseases and Ad vector effectiveness. The innate response uses an array of pathogen recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs). The best-characterized PRRs are the members of the Toll-like receptor family (TLRs); among them, TLR4 is arguably the most studied. Due to the endemic and occasional epidemic nature of human adenovirus (HAd) infections, and the advent of human and nonhuman Ad-derived vectors for shortterm (e.g., vaccines) and long-term (e.g., brain gene transfer) (1, 2) transgene expression, understanding their interaction with the innate immune system is fundamental to better treat HAd diseases and to optimize the efficacy of gene transfer vectors. Studies addressing the interaction of HAds with PRR have demonstrated that these pathogens trigger signals from cytosolic-and/or vesiclecompartmentalized double-stranded DNA sensors (3-6).Wild-type and transgenic mice are commonly used to assess the risk and efficacy of drugs and treatments and have been valuable models from which many paradigms of immunology have been derived. Although there are differences that affect the transcriptional response and functionality of several leukocyte lineages (7, 8) and TLR4 signaling (9), there are many features conserved between human and murine immune systems. Yet a recent pair of studies described contrasting interpretations-using the same data set-of the fidelity of mouse models with respect to mimicking human inflammatory diseases (59, 60).When pathogens are concerned, the results generated in mice can influence therapies in humans. The interaction bet...

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“…6). N. meningitidis LpxL1 LPS, which specifically activates the murine but not human TLR4/ MD2 complex (47), also activated the chTLR4/chMD-2 complex, although the maximum response was reduced compared with the LPS of the parent strain (Fig. 6).…”

Section: Lps Specificity Of the Chtlr4/chmd-2 Complexmentioning

confidence: 98%

Unique Properties of the Chicken TLR4/MD-2 Complex: Selective Lipopolysaccharide Activation of the MyD88-Dependent Pathway

Keestra

Putten

2008

The Journal of Immunology

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125

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During evolution, mammals have evolved a powerful innate immune response to LPS. Chickens are much more resistant to LPS-induced septic shock. Herein we report that chickens sense LPS via orthologs of mammalian TLR4 and myeloid differentiation protein-2 (MD-2) rather than the previously implicated chicken TLR2 isoform type 2 (chTLR2t2) receptor. Cloning and expression of recombinant chTLR4 and chMD-2 in HeLa 57A cells activated NF-κB at concentrations of LPS as low as 100 pg/ml. Differential pairing of chicken and mammalian TLR4 and MD-2 indicated that the protein interaction was species-specific in contrast to the formation of functional human and murine chimeric complexes. The chicken LPS receptor responded to a wide variety of LPS derivatives and to the synthetic lipid A compounds 406 and 506. The LPS specificity resembled the functionality of the murine rather than the human TLR4/MD-2 complex. Polymorphism in chTLR4 (Tyr383His and Gln611Arg) did not influence the LPS response. Interestingly, LPS consistently failed to activate the MyD88-independent induction of IFN-β in chicken cells, in contrast to the TLR3 agonist poly(I:C) that yielded a potent IFN-β response. These results suggest that chicken lack a functional LPS-specific TRAM-TRIF (TRIF-related adapter molecule/TIR-domain-containing adapter-inducing IFN-β) signaling pathway, which may explain their aberrant response to LPS compared with the mammalian species.

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Differential Activation of Human and Mouse Toll-Like Receptor 4 by the Adjuvant Candidate LpxL1 ofNeisseria meningitidis

Abstract: Neisseria meningitidis LpxL1 lipopolysaccharide (LPS) bearing penta-acylated lipid

Cited by 72 publications

References 39 publications

Lipopolysaccharide Engineering in Neisseria meningitidis

Lipopolysaccharide Engineering in Neisseria meningitidis

Human Coagulation Factor X-Adenovirus Type 5 Complexes Poorly Stimulate an Innate Immune Response in Human Mononuclear Phagocytes

Unique Properties of the Chicken TLR4/MD-2 Complex: Selective Lipopolysaccharide Activation of the MyD88-Dependent Pathway

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